Divalproex
Divalproex
Generic Name
Divalproex
Mechanism
- Enhancement of GABAergic transmission
- Inhibits GABA‑transaminase → ↑ intracellular GABA
- Competitive antagonist of GABA‑gated chloride channels → increased neuronal hyperpolarization
- Modulation of glutamatergic activity
- Reduces excitatory glutamate release via sodium‑dependent transporter inhibition
- Blockade of voltage‑dependent ion channels
- Inhibits high‑threshold voltage‑gated Na⁺ channels (rapid inactivation)
- Blocks T‑type Ca²⁺ channels (low‑threshold) → reduced burst firing in thalamocortical neurons
- Inhibition of acetyl‑CoA carboxylase → ↑ fatty‑acid oxidation, contributing to lipid‑mediated neuroprotection
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Pharmacokinetics
- Oral absorption
- Peak concentrations 1–4 h post‑dose; higher with high‑fat meals
- Distribution
- Highly protein‑bound (≈90 % to albumin, α‑1‑acid glycoprotein)
- Extensive tissue penetration; crosses placental barrier & blood–brain barrier
- Metabolism
- Hepatic: glucuronidation, β‑oxidation, ω‑hydroxylation (via CYP2C9/2C19, UGT enzymes)
- Minor non‑enzymatic conversion to 2‑propyl‑valproate
- Elimination
- Primarily renal excretion of metabolites (∼80 %); small fraction unchanged drug (∼5 %)
- Half‑life: 9–18 h (short‑acting), 8–12 h (extended‑release)
- Special Populations
- Pregnancy: placental transfer → teratogenic (spina bifida, cardiac defects)
- Elderly & hepatic impairment: ↑ systemic exposure, necessitate dose reduction
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Indications
- Epilepsy
- Generalized tonic‑clonic, complex partial, absence, myoclonic seizures
- Lennox‑Gastaut & Dravet syndrome adjunctive therapy
- Bipolar Disorder
- Acute mania and maintenance prophylaxis (≤ 3 mg/kg/day)
- Migraine Prophylaxis
- Preventive therapy in frequent episodic or chronic migraine
- Post‑epileptic status (IV preparation available)
- Anticonvulsant rescue (in some regions)
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Contraindications
| Category | Details |
| Contraindicated | Severe hepatic disease, active pancreatitis, known allergy, urea cycle disorders, pregnancy (Category X) |
| Warnings | Hepatotoxicity, pancreatitis, hypertriglyceridemia, teratogenicity, weight gain, hair loss, tremor, thrombocytopenia, elevated ammonia, drug interactions (e.g., carbamazepine, phenytoin, lamotrigine, warfarin) |
| Precautions | Renal impairment, elderly, hypoalbuminemia, alcohol abuse, psychiatric disorders, pregnancy planning |
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Dosing
| Population | Initial Dose | Maintenance Dose | Loading Dose | Formulation | Notes |
| Adult | 500–1000 mg/day (divided) | 1–2 mg/kg/day (max 2000 mg/day) | 20–30 mg/kg (IV) | CR, PR, ER | Titrate by 100–200 mg increments each 1–2 weeks |
| Children (≥2 yrs) | 1–2 mg/kg/day (max 1600 mg/day) | 2–4 mg/kg/day (max 2000 mg/day) | 20–30 mg/kg IV | CR, PR, ER | Weight‑based; monitor hepatic function |
| Pregnancy (avoid) | – | – | – | – | Use strict teratogenicity counseling |
| Breastfeeding | – | – | – | – | Contraindicated; drug excreted in breast milk |
• Extended‑Release (ER): twice daily; improves adherence.
• Concomitant Medications: monitor for drug–drug interactions; may require dose adjustment.
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Monitoring
| Parameter | Frequency | Rationale |
| Liver enzymes (AST/ALT, bilirubin) | Baseline, 2 wks after dose change, then 1–3 months | Detect hepatotoxicity |
| Platelet count | Baseline, 2 wks, then 3–6 months | Monitor thrombocytopenia |
| Serum valproate level | 2 weeks after load, then 1–3 months | Ensure therapeutic range (50–125 µg/mL for epilepsy, 35–125 µg/mL for bipolar) |
| Triglycerides & cholesterol | Baseline, 3 months, annually | Hyperlipidemia risk |
| Renal function | Baseline, annually | Excretory profile |
| Pregnancy test (women of childbearing potential) | Every 3 months | Minimize teratogenic risk |
| Ammonia levels (if encephalopathic signs) | As indicated | Detect hyperammonemia |
| Weight & BMI | Every visit | Monitor weight gain |
| EEG (epilepsy) | Baseline, as clinically indicated | Assess seizure control |
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Clinical Pearls
- Loading Doses: Use the high‑fat fasted loading dose (20–30 mg/kg IV for status epilepticus) to achieve therapeutic levels faster; adjust weight‑based calculations for pediatrics.
- Avoid High‑Fat Meals: After oral intake, high‑fat meals delay absorption; separate dosing by at least 4 hours.
- Protein Binding Insight: In severe hypoalbuminemia (e.g., liver failure), the free fraction rises markedly → increased toxicity → require lower dose.
- Drug Interactions: Lamotrigine is *dramatically* reduced by valproic acid (↓50–75 %); titrate lamotrigine slower and monitor levels.
- Breastfeeding: Valproate is present in human milk (~12–20 % of plasma concentration). Breastfeeding is *contraindicated* unless benefits outweigh risks.
- Pregnancy Safe Alternatives: For women of childbearing potential, consider lithium or atypical antipsychotics for bipolar mania; valproate reserved only if no other options.
- Weight & Lipid Monitoring: 1–3 months after initiation → catch hypertriglyceridemia early; consider statins only after valproate dosing is stable.
- Extended‑Release vs. Immediate‑Release: ER reduces daytime drowsiness and improves tolerability; however, rescue dosing (IV) still requires the *immediate‑release* formulation.
- Non‑Neurotoxicity Note: Low‑dose valproate (50–200 mg/d) in migraine prophylaxis may have less CNS side effects but still monitor LFTs.
- Pancreatitis Prevention: Counsel patients on balanced diet; avoid prolonged fasting, alcohol, and high‑fat meals, especially in the first 8 weeks of therapy.
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• > Key Takeaway:
> Divalproex is a versatile AED but carries significant hepatotoxic, teratogenic, and metabolic risks. Rigorous dosing, monitoring, and patient education are essential to optimize benefit while minimizing harm.